Amyloid Pathology May Be Present Long Before Onset of Dementia

Amyloid may be present as long as 30 years before the onset of dementia, according to findings published in JAMA.

Researchers from Maastricht University in the Netherlands used data meta-analysis of positron emission tomography and cerebrospinal fluid findings to detect biomarkers of amyloid pathology in people with normal cognition, subjective cognitive impairment (SCI), and mild cognitive impairment (MCI). Records were provided for 2,914 people with normal cognition, 697 with SCI, and 3,972 with MCI aged 18 to 100 years.

The researchers found that amyloid pathology increased from age 50 to 90 years from 10% to 40% in people with normal cognition; from 12% to 43% in people with SCI; and from 27% to 71% in people with MCI. Carriers of the APOE-ε4 gene had a two to three times higher prevalence than noncarriers. Fifteen percent of APOE-ε4 carriers with normal cognition were amyloid positive by age 40; 50 years for ε2ε4 carriers; 55 years for ε3ε4 carriers; 65 years for ε3ε3 carriers; and 95 years for ε2ε3 carriers. At 90 years, approximately 40% of the APOE-ε4 noncarriers and more than 80% of APOE-ε4 carriers with normal cognition were amyloid positive. Interestingly, amyloid was more common in highly-educated participants but was not associated with sex or biomarker modality.

“The observation that key risk factors for AD-type dementia are also risk factors for amyloid positivity in cognitively normal persons provides further evidence for the hypothesis that amyloid positivity in these individuals reflects early AD,” the researchers wrote. “Our study also indicates that development of AD pathology can start as early as age 30 years, depending on the APOE genotype. Comparison with prevalence and lifetime risk estimates of AD-type dementia suggests a 20- to 30-year interval between amyloid positivity and dementia, implying that there is a large window of opportunity to start preventive treatments.”

However, the authors point out that follow-up studies need to be conducted since not all people with amyloid pathology develop dementia in their lifetime, and not all people with a clinical diagnosis of Alzheimer's dementia have amyloid pathology.

“Because of the uncertainty about whether and when an amyloid-positive individual without dementia will develop dementia, amyloid positivity in these individuals should not be equated with impending clinical dementia but rather be seen as a risk state,” they wrote. “Our prevalence rates can be used as an inexpensive and noninvasive approach to select persons at risk for amyloid positivity.”

The results highlight the importance of evaluating and monitoring cognitive function in individuals with recent critical illness or major infections, especially if they are already at risk for dementia.